Abstract It is estimated that one million cases of syncope and sudden cardiac death are caused by arrhythmias every year in the United States and Europe. Drug therapy is an option for treating arrhythmias however the efficacy of drug treatments vary depending on the location and types of arrhythmia. Further, heart failure is a contraindication for the drugs used to combat arrhythmia which is a problem considering a large portion of people with heart failure also have arrhythmias. Another treatment option for treating arrhythmia is usage of implantable cardioverter defibrillators and pacemakers. The drawbacks to this type of therapies is that they are invasive and can have poor patient acceptance as well as suboptimal outpatient applicability. There is also the potential for pacing devices to malfunction in the presence of a source of electromagnetic energy. Our main hypothesis is that low-intensity non-ablative ultrasound may offer an alternative for modulation of cardiac electrophysiology. Previous studies and our own preliminary results have shown that cardiac pacing via ultrasound may be possible, however only limited sets of ultrasound parameters have been tested so far. Mechanosensitivity of cardiomyocytes and cardiac tissue is well documented, with multiple biological structures engaged in the response. Yet, mechanistically, very few studies have pursued identification of the molecular correlates of cardiomyocyte response to ultrasound, and no mechanistic studies have been done before in human cardiomyocytes. We have two main specific aims which we wish to achieve for testing our hypothesis. Our first specific aim is to find optimal ultrasound parameters to safely and effectively control cardiac electromechanical activity of human cardiomyocytes, including controlling reversible change in pacing rate, initiation and termination of activity. Our second specific aim is to study molecular mechanisms of cardiac electromechanical response to low-intensity ultrasound stimulation. This work can impact the fields of stem cell biology for cardiac repair and personalized medicine. It can also inspire a development of novel ultrasound in vivo rhythm control devices.